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Comparison of adiponectin, leptin and leptin to adiponectin ratio as diagnostic marker for metabolic syndrome in older adults of Chinese major cities
diabetes research and clinical practice 84 (2009) 27–33
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Diabetes Research and Clinical Practice journal homepage: www.elsevier.com/locate/diabres
Comparison of adiponectin, leptin and leptin to adiponectin ratio as diagnostic marker for metabolic syndrome in older adults of Chinese major cities Qin Zhuo a, Zhiqiang Wang b, Ping Fu a, Jianhua Piao a, Yuan Tian a, Jie Xu a, Xiaoguang Yang a,* a
National Institute for Nutrition and Food Safety, Chinese Center for Disease Control and Prevention, No. 29 Nanwei Road, Xuanwu District, Beijing 100050, China b Center for Chronic Disease, School of Medicine, University of Queensland, Australia
article info
abstract
Article history:
The aim of this study was to compare the strength of association between metabolic
Received 12 August 2008
syndrome (MetS) and adiponectin, leptin and leptin to adiponectin ratio (L/A) in older
Received in revised form
Chinese. This study included 950 males (220 with MetS) and 1096 females (452 with MetS),
23 December 2008
aged 60–96 years from 18 major cities of the 2002 China National Nutrition and Health
Accepted 29 December 2008
Survey. The associations of adiponectin, leptin and L/A with components of MetS and MetS
Published on line 31 January 2009
were examined using logistic regression and the receiver operating characteristic (ROC) curves. The correlation coefficients of MetS components except fasting glucose with leptin
Keywords:
were similar to those with L/A and higher than those with adiponectin. After adjusting for
Adiponectin
age and BMI, the odds ratio for MetS corresponding to 1 SD change in L/A was higher than
Leptin
those for leptin and adiponectin. L/A had highest area under the curve (AUC) for MetS.
Leptin to adiponectin ratio
However, there was no statistically significant difference in AUC between leptin and L/A,
Metabolic syndrome
and both indices produced a significantly higher AUC than adiponectin. In conclusion, L/A
Chinese older adults
and leptin may be better diagnostic markers for MetS than adiponectin. After adjusting for BMI, L/A has better ability for correctly classifying subjects with and without MetS than adiponectin or leptin alone. # 2009 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
The adipose tissue has been found to be an important endocrine organ in recent years. It secretes several bioactivity molecules termed adipokines regulating whole body metabolism and immune responses [1,2]. Adiponectin is an important adipokine and abundant in circulation. Unlike other adipokines, which increase with excess body fat mass, the adiponectin concentrations decreases in obese people, as well as in patients with diabetes
mellitus (DM), hypertension, dyslipidemia and metabolic syndrome (MetS) [3–15]. Leptin is another important adipokine identified in 1994 [16]. It regulates of the mass of adipose tissue and body weight by inhibiting food intake and stimulating energy expenditure [17,18]. Many studies suggested the leptin levels were positively correlated with obesity, DM, hypertension and MetS [19–21]. Recently, some researchers proposed the ratio of leptin to adiponectin (L/A) as a good marker for obesity, insulin
* Corresponding author. Tel.: +86 10 83132798; fax: +86 10 83132808. E-mail address: [email protected] (X. Yang). 0168-8227/$ – see front matter # 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2008.12.019
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diabetes research and clinical practice 84 (2009) 27–33
resistance and MetS in comparison to the adiponectin and leptin levels alone [22,23]. It appears sensible since the levels of the two adipokines are associated with metabolic diseases in the opposite directions. However, the study of Mojiminyi et al. showed the adiponectin was better than leptin and L/A for identifying obese subjects with the MetS [24]. So far, few studies have compared the relative importance of adiponectin, leptin and L/A for correctly classifying subjects with and without MetS. It is important to make clear the diagnostic power of the two adipokines for future clinical use. Epidemiological studies have shown that the prevalence of MetS varies with gender, age, ethnic background and residence. The prevalence of MetS increases with age and is higher in urban than in rural. Therefore, the old population in cities has higher risk for MetS than other populations [25–27]. It is important to conduct more research work of MetS focusing on this population. Therefore, in present study, we compared the strength of association between MetS and adiponectin, leptin and L/A and the ability of adiponectin, leptin and L/A for correctly classifying subjects with and without MetS in older adults of Chinese major cities based on the data of 2002 China National Nutrition and Health Survey (CNHS).
2.
Materials and methods
2.1.
Study population
The China National Nutrition and Health Survey in 2002 was the first comprehensive survey in the field of nutrition and health in China [28]. This survey was conducted from August to December 2002 and covered all 31 provinces, autonomous regions and municipalities directly under the Central Government throughout China (except Taiwan, Hong Kong and Macao). The participants were recruited using a stratified multistage cluster sampling design. The country was divided into six strata: major cities, small to medium sized cities, 1st class rural areas, 2nd class rural areas, 3rd class rural areas and 4th class rural areas according to their characteristics of economy and social development using data from the China National Bureau of Statistics. The first stage of sampling involved the random selection of 22 districts (in urban) or counties (in rural) from each of the six strata. The second stage involved the random selection of three neighborhoods (in urban) or townships (in rural) from each of the selected districts/counties. From each of the neighborhoods or townships, two residential committees (in urban) or villages (in rural) were randomly selected from which 90 households were randomly sampled from each village. A total of 801 residential committees or villages and 73,346 families were sampled. The study participants were defined as permanent residents of the households with a record in the household registration. One third of the participants took part in medical examination and diets survey. Fasting blood samples of these participants were drawn and the plasma samples were properly stored at 70 8C. All the sample tubes were pasted with unique blood ID number that could be retrieved. In this study, we focused on data from all initially sampled 18 major cities: Beijing, Shanghai, Tianjin, Chongqing, Harbin, Shenyang, Dalian,
Jinan, Qingdao, Ningbo, Nanjing, Guangzhou, Shenzhen, Zhengzhou, Chengdu, Xian, Wuhan and Xiamen. We retrieved 2280 eligible plasma samples of adults aged 60–96 years from those cities and 234 participants were excluded due to insufficient plasma samples for adiponectin or leptin testing. The final data included 2046 participants (about 90%). The participants provided informed consent for the original survey and further studies, and the project was approved by the Academic Committee of the Institute of Nutrition and Food Safety of Chinese Center for Disease Control and Prevention.
2.2.
Data collections and measurements
During the National Nutrition and Health Survey, blood pressure was measured by uniform mercury column sphygmomanometers. Body height and weight were measured with standiometers and digital scales to the nearest 1 mm and 0.1 kg, respectively. Body mass index (BMI) was calculated as weight (kg)/[height (m)]2. Waist circumference was measured with tape measure to the nearest 0.1 cm, as half-way between the lower border of the ribs and the Iliac crest with the tape horizontal. High-density lipoprotein cholesterol (HDL-C), triglycerides (TG), total cholesterol, low-density lipoprotein cholesterol (LDL-C) and glucose were also measured by uniform reagents. In this study, plasma leptin (ng/ml) and adiponectin (mg/ml) concentrations were determined with commercially available ELISA kits (Phoenix Pharmaceuticals, Inc., Belmont, CA, USA). All procedures described in the manufacturer’s instructions were followed with quality control parameters within the expected range recommended by the manufacturer. Every tenth sample was duplicated on the same plate. The minimum detectable concentration of leptin kit is 0.25 ng/ml with the intra-assay CV <3% and the inter-assay CV <10%. The minimum detectable concentration of adiponectin kit is 0.15 ng/ml, with the intra-assay CV ranged from 3 to 6% and the inter-assay CV <10%.
2.3.
Definition of MetS
Subjects were grouped according to the International Diabetes Federation (IDF) definition of MetS. This criteria required the central obesity as the essential component, i.e. waist circumferences 90 cm in men or 80 cm in women (Chinese population waist circumference cutoffs) and plus two or more of the following four disturbances: (1) triglycerides 1.7 mmmol/l or drug treatment for elevated TG; (2) HDL-C <1.03 mmol/l in men or <1.29 mmol/l in women or drug treatment for decreased HDL-C; (3) systolic blood pressure (SBP) 130 mmHg or diastolic blood pressure (DBP) 85 mmHg or drug treatment for hypertension; (4) fasting blood glucose 5.6 mmol/l or drug treatment for DM.
2.4.
Statistical analysis
Continuous variables were presented as means and 95% confidence intervals (CIs). Skewed continuous variables such as adiponectin, leptin and leptin to adioponectin ratio (L/A) were log-transformed. Differences between subjects with or without MetS were compared by t-test. Relations between adiponectin, leptin and L/A with the components of MetS were
diabetes research and clinical practice 84 (2009) 27–33
analyzed by Pearson’s correlation analysis. Since adiponectin, leptin and L/A had different measurement units, we converted the original measurements to SD scores—z scores to compare the associations of the three indices with MetS using logistic regression. To compare the diagnostic strength of the adiponectin, leptin and L/A for classifying subjects with and without MetS, the receiver operating characteristic (ROC) analysis was performed and the areas under the curve (AUCs) among adiponectin, leptin, and L/A were compared by a nonparametric approach [29]. Statistical tests were 2-sided and p-value <0.05 was considered as statistical significance. All data management and statistical analyses were performed with Stata statistical software version 10 [30].
3.
Results
3.1.
Characteristics of the subjects with or without MetS
Table 1 summarized the characteristics of the participants grouped by sex and the MetS status. Compared with the subjects with MetS, the subjects without the MetS had lower BMI, waist circumference, blood pressure, TG, fasting blood glucose, leptin and L/A and higher HDL-C and adiponectin levels in both sexes (all p < 0.0001). The geometric means of adiponectin and leptin were higher in women than in men.
3.2. Correlations of adiponectin, leptin and L/A with components of MetS Correlation coefficients between adiponectin, leptin and L/A with the components of MetS are presented in Table 2. BMI, waist circumference, SBP, DBP, FBG, HDL-C and TG were all correlated significantly with adiponectin, leptin and L/A in both men and women except for SBP and DBP which were not significantly correlated with adiponectin in men. The correlation coefficients of BMI, waist circumference, SBP and DBP with leptin and L/A were higher than those with adiponectin.
3.3. Associations between adiponectin, leptin and L/A with MetS Table 3 shows ORs for adiponectin, leptin and L/A with MetS. The crude odds ratios indicate that adiponectin, leptin and L/A were significantly associated with the MetS (all p < 0.001). Corresponding to 1 SD decrease in adiponectin or 1 SD increase in leptin and L/A, odds ratios were higher for leptin and L/A than for adiponectin in both sexes. After adjusting for age and BMI, the ORs decreased substantially, the association of MetS with all indices remained significant except that with leptin in men. The ORs of L/A in both sexes were higher than those of adiponectin and leptin.
3.4. ROC curve of adiponectin, leptin and L/A for the detection of MetS Fig. 1 depicts the ROC curve and area under the curve (AUC) of adiponectin, leptin and L/A for detecting of MetS by sex. The L/ A had relatively high sensitivity, specificity and AUC value. The ROC analysis demonstrated significant differences
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( p < 0.001) between the diagnostic efficiency of L/A and adiponectin in both sexes, and the difference between L/A and leptin was not statistically significant ( p = 0.073 in male and p = 0.396 in female).
4.
Discussion
In this study, we found that L/A and leptin are more strongly associated with MetS and its components than adiponectin with them. This implies that L/A and leptin are better biomarkers for the risk of MetS than adiponectin. After adjusting for BMI, the L/A has better ability for correctly classifying subjects with and without MetS than adiponectin and leptin alone. Adiponectin and leptin are two important adipokines exclusively released from adipose tissues. Cumulative evidences showed that the two adipokines were closely correlated with MetS in different populations and could be useful as diagnostic markers of MetS [14,15,19,31–36]. In our study, we confirmed the adiponectin levels were significantly lower and the leptin concentrations were higher in people with MetS. Because adiponectin and leptin correlated with MetS and its related components in opposite manner, some researchers proposed that the L/A could be more useful for predicting MetS and related diseases than adiponectin and leptin alone [22,37,38]. However, Mojiminiyi et al. reported the adiponectin had higher diagnostic efficiency for the detection of MetS than leptin and L/A [24]. Identifying a better predictor for the MetS can be useful in clinical settings. To our knowledge, this was the first large-scale population based study to compare the diagnostic efficiency of adiponectin, leptin and L/A in older Chinese adults. We found although adiponectin was significantly correlated with the components of MetS such as BMI, waist circumference, FBG, HDL-C, TG, the correlation coefficients were all lower than those of leptin and L/A except FBG. However, the leptin and L/ A were significantly correlated with each component of MetS including SBP and DBP, and the correlation coefficients of leptin and L/A were similar. ROC curves further confirmed the leptin and L/A are better biomarkers for MetS than adiponectin. Both the adjusted odds ratios and AUC were higher for L/A than for either leptin or adiponectin alone in both sexes, suggesting that this index with both leptin and adiponectin had a better ability to differentiate individuals with and without MetS. BMI may play an important role in the relationship of leptin with MetS especially in men. After the adjustment for age and BMI, the ORs between leptin and MetS decreased substantially. This phenomenon suggests the relationship between leptin and MetS is mainly mediated by obesity. On the other hand, the adjusted ORs between adiponectin and MetS only attenuated slightly in both sexes, suggesting that adiponectin is associated with MetS independent of BMI. There were few studies comparing the strength of the associations of adiponectin and leptin with MetS. Moiminiyi et al. proposed the adiponectin showed higher diagnostic efficiency for the detection of MetS than leptin and L/A in 135 Kuwaiti patients with type 2 diabetes mellitus [24]. However, the results of Kumagai et al. showed L/A was a good biomarker
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diabetes research and clinical practice 84 (2009) 27–33
Table 1 – Characteristics of the participants. Variable
MetS negative
MetS positive
p-Value
Male Age (years) BMI (kg/m2) Waist (cm) SBP (mmHg) DBP (mmHg) TG (mmol/l) HDL-C (mmol/l) TC (mmol/l) LDL-C (mmol/l) FBG (mmol/l) Leptin (ng/l) Adiponectin (mg/l) L/A
N = 730 68.6 (68.2, 69.1) 23.6 (23.4, 23.8) 83.3 (82.6, 83.9) 137 (135, 138) 82 (81, 83) 1.08 (1.04, 1.12) 1.31 (1.29, 1.33) 4.34 (4.27, 4.40) 2.50 (2.44, 2.55) 5.26 (5.16, 5.37) 2.58 (2.30, 2.89) 11.83 (11.25, 12.44) 0.22 (0.19, 0.25)
N = 220 68.3 (67.5, 69.1) 27.9 (27.5, 28.2) 97.5 (96.7, 98.3) 148 (145, 150) 87 (85, 88) 1.49 (1.40, 1.58) 1.09 (1.06, 1.12) 4.29 (4.16, 4.43) 2.46 (2.35, 2.57) 6.30 (6.00, 6.61) 7.88 (6.98, 8.89) 7.76 (7.11, 8.48) 1.01 (0.88, 1.18)
0.4700 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.5323 0.5705 <0.0001 <0.0001 <0.0001 <0.0001
Female Age (years) BMI (kg/m2) Waist (cm) SBP (mmHg) DBP (mmHg) TG (mmol/l) HDL-C (mmol/l) TC (mmol/l) LDL-C (mmol/l) FBG (mmol/l) Leptin (ng/l) Adiponectin (mg/l) L/A
N = 644 68.1 (67.6, 68.6) 23.7 (23.5, 24.0) 79.3 (78.6, 80.0) 135 (133, 136) 79 (78, 79) 1.16 (1.13, 1.19) 1.47 (1.45, 1.49) 4.77 (4.70, 4.84) 2.72 (2.66, 2.78) 5.21 (5.10, 5.32) 9.52 (8.83, 10.23) 14.83 (14.10, 15.60) 0.64 (0.58, 0.71)
N = 452 68.1 (67.5, 68.6) 27.2 (26.9, 27.5) 90.5 (89.8, 91.2) 150 (148, 152) 84 (83, 85) 1.67 (1.59, 1.75) 1.23 (1.20, 1.25) 4.76 (4.66, 4.86) 2.71 (2.63, 2.79) 6.38 (6.16, 6.61) 17.78 (16.83, 18.77) 11.08 (10.45, 11.74) 1.60 (1.48, 1.74)
0.8239 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.9133 0.8825 <0.0001 <0.0001 <0.0001 <0.0001
Data were presented as mean (95% CI). Abbreviations: SBP, systolic blood pressure; DBP, systolic blood pressure; BMI, body mass index; FBG, fasting blood glucose; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol.
for the prevalence of MetS in comparison to the adiponectin and leptin levels alone in 77 Japanese male patients with diabetes mellitus [38]. In our study on older Chinese adults from the general population, the ability of leptin and L/A for
correctly classifying subjects with or without MetS are similar and better than adiponectin, and after adjusting for BMI, the L/ A showed to be better biomarker for MetS. The discrepancies may be due to the difference in the characteristics of the study
Table 2 – Correlation coefficients between adiponectin, leptin and leptin to adiponectin ratio with the components of MetS. Adiponectin r
Leptin p
r
L/A p
r
p
Men BMI Waist DBP SBP FBG HDL-C TG
0.254 0.285 0.047 0.015 0.118 0.238 0.204
<0.0001 <0.0001 0.1461 0.6418 0.0003 <0.0001 <0.0001
0.616 0.612 0.169 0.147 0.081 0.304 0.280
<0.0001 <0.0001 <0.0001 <0.0001 0.0123 <0.0001 <0.0001
0.608 0.617 0.158 0.127 0.113 0.343 0.311
<0.0001 <0.0001 <0.0001 0.0001 <0.0005 <0.0001 <0.0001
Women BMI Waist DBP SBP FBG HDL-C TG
0.177 0.216 0.106 0.060 0.121 0.255 0.186
<0.0001 <0.0001 0.0004 0.0481 0.0001 <0.0001 <0.0001
0.573 0.569 0.172 0.161 0.043 0.165 0.261
<0.0001 <0.0001 <0.0001 <0.0001 0.1572 <0.0001 <0.0001
0.511 0.529 0.180 0.147 0.096 0.259 0.289
<0.0001 <0.0001 <0.0001 <0.0001 0.0015 <0.0001 <0.0001
Abbreviations: BMI, body mass index; SBP, systolic blood pressure; DBP, systolic blood pressure; FBG, fasting blood glucose; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; L/A, leptin to adiponectin ratio.
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diabetes research and clinical practice 84 (2009) 27–33
Table 3 – Odds ratios and 95% confidence intervals for adiponectin, leptin, and leptin to adiponectin ratio with MetS. Variable
Adjusteda
Crude OR (95% CI)
p
OR (95% CI)
Male Adiponectin, 1 SD decrease Leptin, 1 SD increase L/A, 1 SD increase
1.79 (1.54, 2.08) 3.49 (2.68, 4.55) 3.71 (2.90, 4.74)
<0.001 <0.001 <0.001
1.61 (1.33, 1.95) 1.29 (0.96, 1.74) 1.83 (1.38, 2.45)
<0.001 0.089 <0.001
Female Adiponectin, 1 SD decrease Leptin, 1 SD increase L/A, 1 SD increase
1.58 (1.38, 1.81) 4.56 (3.46, 6.01) 3.63 (2.90, 4.55)
<0.001 <0.001 <0.001
1.48 (1.28, 1.73) 2.06 (1.53, 2.79) 2.32 (1.82, 2.96)
<0.001 <0.001 <0.001
a
p
Adjusted for age and BMI.
participants. The subjects in Mojiminiyi et al.’s study were patients with T2DM while the participants of Kumagai et al.’s study were male with either IGT or T2DM. Our participants were recruited from the residents from the general population. And the studies based on small-sizes may produce inconsistent results. More studies were warranted to elucidate which biomarker is better to differentiate individuals with and without MetS. Some lifestyle factors such as diet, smoking, alcohol drinking, and physical activity are thought to be important confounding factors of MetS. We compared the characteristics of participants between those with and without MetS. There were no significant differences between participants with and without MetS in both genders except for alcohol intake in men. After adjusting for those factors, the odds ratios remained similar. Therefore, we did not further adjust for those factors. We also performed the analyses on subsets data from the subjects who were not under medication for diabetes, hypertension or dyslipidemia and those who were free from DM. We also conducted the same analyses on the same participants using the updated ATP III definition for MetS proposed by American Heart Association/National Heart,
Lung, and Blood Institute (AHA/NHLBI) [39]. The results (data not shown) were similar to those of this paper. There are several limits in this study. Firstly, our study is cross-sectional and therefore it does not establish a cause and effect relationship. Secondly, since our study participants were older adults selected from 18 major cities in China, whether our findings can be deduced to other populations needs to be further assessed. Thirdly, there were different molecular weight multimer forms of adiponectin in the circulation, and some studies suggested the high molecular weight (HMW) multimers are the active forms of adiponectin, and are more useful than total adiponectin in evaluating the MetS and IR [40]. Though the results in this study showed leptin was a better biomarker for MetS than the total adiponectin, the roles of HMW multimers may be weakened by including adiponectin of low molecular weight. Further studies on comparison of HMW adiponectin and leptin associations with MetS are warranted. In conclusion, this study investigated the strength of adiponectin, leptin and L/A with MetS in older adults in major cities in China. The L/A and leptin were stronger associated with metabolic syndrome and its components than adipo-
Fig. 1 – Receiver operating characteristic curve for MetS by adiponectin, leptin and L/A stratified by sex.
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diabetes research and clinical practice 84 (2009) 27–33
nectin with them. Our results imply that the L/A and leptin are better diagnostic markers for MetS than adiponectin. After adjusting for BMI, the L/A has better ability for correctly classifying subjects with and without MetS than adiponectin and leptin alone. Further studies are needed to elucidate our findings in different populations.
Conflict of interest None.
Acknowledgements This work was supported by research grant from National Natural Science Foundation of China (30671750). Zhiqiang Wang is supported by National Health and Medical Research Council of Australia (511013). The authors thank to all staff and participants of China National Nutrition and Health Survey in 2002.
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Contents lists available at ScienceDirect
Diabetes Research and Clinical Practice journal homepage: www.elsevier.com/locate/diabres
Comparison of adiponectin, leptin and leptin to adiponectin ratio as diagnostic marker for metabolic syndrome in older adults of Chinese major cities Qin Zhuo a, Zhiqiang Wang b, Ping Fu a, Jianhua Piao a, Yuan Tian a, Jie Xu a, Xiaoguang Yang a,* a
National Institute for Nutrition and Food Safety, Chinese Center for Disease Control and Prevention, No. 29 Nanwei Road, Xuanwu District, Beijing 100050, China b Center for Chronic Disease, School of Medicine, University of Queensland, Australia
article info
abstract
Article history:
The aim of this study was to compare the strength of association between metabolic
Received 12 August 2008
syndrome (MetS) and adiponectin, leptin and leptin to adiponectin ratio (L/A) in older
Received in revised form
Chinese. This study included 950 males (220 with MetS) and 1096 females (452 with MetS),
23 December 2008
aged 60–96 years from 18 major cities of the 2002 China National Nutrition and Health
Accepted 29 December 2008
Survey. The associations of adiponectin, leptin and L/A with components of MetS and MetS
Published on line 31 January 2009
were examined using logistic regression and the receiver operating characteristic (ROC) curves. The correlation coefficients of MetS components except fasting glucose with leptin
Keywords:
were similar to those with L/A and higher than those with adiponectin. After adjusting for
Adiponectin
age and BMI, the odds ratio for MetS corresponding to 1 SD change in L/A was higher than
Leptin
those for leptin and adiponectin. L/A had highest area under the curve (AUC) for MetS.
Leptin to adiponectin ratio
However, there was no statistically significant difference in AUC between leptin and L/A,
Metabolic syndrome
and both indices produced a significantly higher AUC than adiponectin. In conclusion, L/A
Chinese older adults
and leptin may be better diagnostic markers for MetS than adiponectin. After adjusting for BMI, L/A has better ability for correctly classifying subjects with and without MetS than adiponectin or leptin alone. # 2009 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
The adipose tissue has been found to be an important endocrine organ in recent years. It secretes several bioactivity molecules termed adipokines regulating whole body metabolism and immune responses [1,2]. Adiponectin is an important adipokine and abundant in circulation. Unlike other adipokines, which increase with excess body fat mass, the adiponectin concentrations decreases in obese people, as well as in patients with diabetes
mellitus (DM), hypertension, dyslipidemia and metabolic syndrome (MetS) [3–15]. Leptin is another important adipokine identified in 1994 [16]. It regulates of the mass of adipose tissue and body weight by inhibiting food intake and stimulating energy expenditure [17,18]. Many studies suggested the leptin levels were positively correlated with obesity, DM, hypertension and MetS [19–21]. Recently, some researchers proposed the ratio of leptin to adiponectin (L/A) as a good marker for obesity, insulin
* Corresponding author. Tel.: +86 10 83132798; fax: +86 10 83132808. E-mail address: [email protected] (X. Yang). 0168-8227/$ – see front matter # 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2008.12.019
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diabetes research and clinical practice 84 (2009) 27–33
resistance and MetS in comparison to the adiponectin and leptin levels alone [22,23]. It appears sensible since the levels of the two adipokines are associated with metabolic diseases in the opposite directions. However, the study of Mojiminyi et al. showed the adiponectin was better than leptin and L/A for identifying obese subjects with the MetS [24]. So far, few studies have compared the relative importance of adiponectin, leptin and L/A for correctly classifying subjects with and without MetS. It is important to make clear the diagnostic power of the two adipokines for future clinical use. Epidemiological studies have shown that the prevalence of MetS varies with gender, age, ethnic background and residence. The prevalence of MetS increases with age and is higher in urban than in rural. Therefore, the old population in cities has higher risk for MetS than other populations [25–27]. It is important to conduct more research work of MetS focusing on this population. Therefore, in present study, we compared the strength of association between MetS and adiponectin, leptin and L/A and the ability of adiponectin, leptin and L/A for correctly classifying subjects with and without MetS in older adults of Chinese major cities based on the data of 2002 China National Nutrition and Health Survey (CNHS).
2.
Materials and methods
2.1.
Study population
The China National Nutrition and Health Survey in 2002 was the first comprehensive survey in the field of nutrition and health in China [28]. This survey was conducted from August to December 2002 and covered all 31 provinces, autonomous regions and municipalities directly under the Central Government throughout China (except Taiwan, Hong Kong and Macao). The participants were recruited using a stratified multistage cluster sampling design. The country was divided into six strata: major cities, small to medium sized cities, 1st class rural areas, 2nd class rural areas, 3rd class rural areas and 4th class rural areas according to their characteristics of economy and social development using data from the China National Bureau of Statistics. The first stage of sampling involved the random selection of 22 districts (in urban) or counties (in rural) from each of the six strata. The second stage involved the random selection of three neighborhoods (in urban) or townships (in rural) from each of the selected districts/counties. From each of the neighborhoods or townships, two residential committees (in urban) or villages (in rural) were randomly selected from which 90 households were randomly sampled from each village. A total of 801 residential committees or villages and 73,346 families were sampled. The study participants were defined as permanent residents of the households with a record in the household registration. One third of the participants took part in medical examination and diets survey. Fasting blood samples of these participants were drawn and the plasma samples were properly stored at 70 8C. All the sample tubes were pasted with unique blood ID number that could be retrieved. In this study, we focused on data from all initially sampled 18 major cities: Beijing, Shanghai, Tianjin, Chongqing, Harbin, Shenyang, Dalian,
Jinan, Qingdao, Ningbo, Nanjing, Guangzhou, Shenzhen, Zhengzhou, Chengdu, Xian, Wuhan and Xiamen. We retrieved 2280 eligible plasma samples of adults aged 60–96 years from those cities and 234 participants were excluded due to insufficient plasma samples for adiponectin or leptin testing. The final data included 2046 participants (about 90%). The participants provided informed consent for the original survey and further studies, and the project was approved by the Academic Committee of the Institute of Nutrition and Food Safety of Chinese Center for Disease Control and Prevention.
2.2.
Data collections and measurements
During the National Nutrition and Health Survey, blood pressure was measured by uniform mercury column sphygmomanometers. Body height and weight were measured with standiometers and digital scales to the nearest 1 mm and 0.1 kg, respectively. Body mass index (BMI) was calculated as weight (kg)/[height (m)]2. Waist circumference was measured with tape measure to the nearest 0.1 cm, as half-way between the lower border of the ribs and the Iliac crest with the tape horizontal. High-density lipoprotein cholesterol (HDL-C), triglycerides (TG), total cholesterol, low-density lipoprotein cholesterol (LDL-C) and glucose were also measured by uniform reagents. In this study, plasma leptin (ng/ml) and adiponectin (mg/ml) concentrations were determined with commercially available ELISA kits (Phoenix Pharmaceuticals, Inc., Belmont, CA, USA). All procedures described in the manufacturer’s instructions were followed with quality control parameters within the expected range recommended by the manufacturer. Every tenth sample was duplicated on the same plate. The minimum detectable concentration of leptin kit is 0.25 ng/ml with the intra-assay CV <3% and the inter-assay CV <10%. The minimum detectable concentration of adiponectin kit is 0.15 ng/ml, with the intra-assay CV ranged from 3 to 6% and the inter-assay CV <10%.
2.3.
Definition of MetS
Subjects were grouped according to the International Diabetes Federation (IDF) definition of MetS. This criteria required the central obesity as the essential component, i.e. waist circumferences 90 cm in men or 80 cm in women (Chinese population waist circumference cutoffs) and plus two or more of the following four disturbances: (1) triglycerides 1.7 mmmol/l or drug treatment for elevated TG; (2) HDL-C <1.03 mmol/l in men or <1.29 mmol/l in women or drug treatment for decreased HDL-C; (3) systolic blood pressure (SBP) 130 mmHg or diastolic blood pressure (DBP) 85 mmHg or drug treatment for hypertension; (4) fasting blood glucose 5.6 mmol/l or drug treatment for DM.
2.4.
Statistical analysis
Continuous variables were presented as means and 95% confidence intervals (CIs). Skewed continuous variables such as adiponectin, leptin and leptin to adioponectin ratio (L/A) were log-transformed. Differences between subjects with or without MetS were compared by t-test. Relations between adiponectin, leptin and L/A with the components of MetS were
diabetes research and clinical practice 84 (2009) 27–33
analyzed by Pearson’s correlation analysis. Since adiponectin, leptin and L/A had different measurement units, we converted the original measurements to SD scores—z scores to compare the associations of the three indices with MetS using logistic regression. To compare the diagnostic strength of the adiponectin, leptin and L/A for classifying subjects with and without MetS, the receiver operating characteristic (ROC) analysis was performed and the areas under the curve (AUCs) among adiponectin, leptin, and L/A were compared by a nonparametric approach [29]. Statistical tests were 2-sided and p-value <0.05 was considered as statistical significance. All data management and statistical analyses were performed with Stata statistical software version 10 [30].
3.
Results
3.1.
Characteristics of the subjects with or without MetS
Table 1 summarized the characteristics of the participants grouped by sex and the MetS status. Compared with the subjects with MetS, the subjects without the MetS had lower BMI, waist circumference, blood pressure, TG, fasting blood glucose, leptin and L/A and higher HDL-C and adiponectin levels in both sexes (all p < 0.0001). The geometric means of adiponectin and leptin were higher in women than in men.
3.2. Correlations of adiponectin, leptin and L/A with components of MetS Correlation coefficients between adiponectin, leptin and L/A with the components of MetS are presented in Table 2. BMI, waist circumference, SBP, DBP, FBG, HDL-C and TG were all correlated significantly with adiponectin, leptin and L/A in both men and women except for SBP and DBP which were not significantly correlated with adiponectin in men. The correlation coefficients of BMI, waist circumference, SBP and DBP with leptin and L/A were higher than those with adiponectin.
3.3. Associations between adiponectin, leptin and L/A with MetS Table 3 shows ORs for adiponectin, leptin and L/A with MetS. The crude odds ratios indicate that adiponectin, leptin and L/A were significantly associated with the MetS (all p < 0.001). Corresponding to 1 SD decrease in adiponectin or 1 SD increase in leptin and L/A, odds ratios were higher for leptin and L/A than for adiponectin in both sexes. After adjusting for age and BMI, the ORs decreased substantially, the association of MetS with all indices remained significant except that with leptin in men. The ORs of L/A in both sexes were higher than those of adiponectin and leptin.
3.4. ROC curve of adiponectin, leptin and L/A for the detection of MetS Fig. 1 depicts the ROC curve and area under the curve (AUC) of adiponectin, leptin and L/A for detecting of MetS by sex. The L/ A had relatively high sensitivity, specificity and AUC value. The ROC analysis demonstrated significant differences
29
( p < 0.001) between the diagnostic efficiency of L/A and adiponectin in both sexes, and the difference between L/A and leptin was not statistically significant ( p = 0.073 in male and p = 0.396 in female).
4.
Discussion
In this study, we found that L/A and leptin are more strongly associated with MetS and its components than adiponectin with them. This implies that L/A and leptin are better biomarkers for the risk of MetS than adiponectin. After adjusting for BMI, the L/A has better ability for correctly classifying subjects with and without MetS than adiponectin and leptin alone. Adiponectin and leptin are two important adipokines exclusively released from adipose tissues. Cumulative evidences showed that the two adipokines were closely correlated with MetS in different populations and could be useful as diagnostic markers of MetS [14,15,19,31–36]. In our study, we confirmed the adiponectin levels were significantly lower and the leptin concentrations were higher in people with MetS. Because adiponectin and leptin correlated with MetS and its related components in opposite manner, some researchers proposed that the L/A could be more useful for predicting MetS and related diseases than adiponectin and leptin alone [22,37,38]. However, Mojiminiyi et al. reported the adiponectin had higher diagnostic efficiency for the detection of MetS than leptin and L/A [24]. Identifying a better predictor for the MetS can be useful in clinical settings. To our knowledge, this was the first large-scale population based study to compare the diagnostic efficiency of adiponectin, leptin and L/A in older Chinese adults. We found although adiponectin was significantly correlated with the components of MetS such as BMI, waist circumference, FBG, HDL-C, TG, the correlation coefficients were all lower than those of leptin and L/A except FBG. However, the leptin and L/ A were significantly correlated with each component of MetS including SBP and DBP, and the correlation coefficients of leptin and L/A were similar. ROC curves further confirmed the leptin and L/A are better biomarkers for MetS than adiponectin. Both the adjusted odds ratios and AUC were higher for L/A than for either leptin or adiponectin alone in both sexes, suggesting that this index with both leptin and adiponectin had a better ability to differentiate individuals with and without MetS. BMI may play an important role in the relationship of leptin with MetS especially in men. After the adjustment for age and BMI, the ORs between leptin and MetS decreased substantially. This phenomenon suggests the relationship between leptin and MetS is mainly mediated by obesity. On the other hand, the adjusted ORs between adiponectin and MetS only attenuated slightly in both sexes, suggesting that adiponectin is associated with MetS independent of BMI. There were few studies comparing the strength of the associations of adiponectin and leptin with MetS. Moiminiyi et al. proposed the adiponectin showed higher diagnostic efficiency for the detection of MetS than leptin and L/A in 135 Kuwaiti patients with type 2 diabetes mellitus [24]. However, the results of Kumagai et al. showed L/A was a good biomarker
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diabetes research and clinical practice 84 (2009) 27–33
Table 1 – Characteristics of the participants. Variable
MetS negative
MetS positive
p-Value
Male Age (years) BMI (kg/m2) Waist (cm) SBP (mmHg) DBP (mmHg) TG (mmol/l) HDL-C (mmol/l) TC (mmol/l) LDL-C (mmol/l) FBG (mmol/l) Leptin (ng/l) Adiponectin (mg/l) L/A
N = 730 68.6 (68.2, 69.1) 23.6 (23.4, 23.8) 83.3 (82.6, 83.9) 137 (135, 138) 82 (81, 83) 1.08 (1.04, 1.12) 1.31 (1.29, 1.33) 4.34 (4.27, 4.40) 2.50 (2.44, 2.55) 5.26 (5.16, 5.37) 2.58 (2.30, 2.89) 11.83 (11.25, 12.44) 0.22 (0.19, 0.25)
N = 220 68.3 (67.5, 69.1) 27.9 (27.5, 28.2) 97.5 (96.7, 98.3) 148 (145, 150) 87 (85, 88) 1.49 (1.40, 1.58) 1.09 (1.06, 1.12) 4.29 (4.16, 4.43) 2.46 (2.35, 2.57) 6.30 (6.00, 6.61) 7.88 (6.98, 8.89) 7.76 (7.11, 8.48) 1.01 (0.88, 1.18)
0.4700 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.5323 0.5705 <0.0001 <0.0001 <0.0001 <0.0001
Female Age (years) BMI (kg/m2) Waist (cm) SBP (mmHg) DBP (mmHg) TG (mmol/l) HDL-C (mmol/l) TC (mmol/l) LDL-C (mmol/l) FBG (mmol/l) Leptin (ng/l) Adiponectin (mg/l) L/A
N = 644 68.1 (67.6, 68.6) 23.7 (23.5, 24.0) 79.3 (78.6, 80.0) 135 (133, 136) 79 (78, 79) 1.16 (1.13, 1.19) 1.47 (1.45, 1.49) 4.77 (4.70, 4.84) 2.72 (2.66, 2.78) 5.21 (5.10, 5.32) 9.52 (8.83, 10.23) 14.83 (14.10, 15.60) 0.64 (0.58, 0.71)
N = 452 68.1 (67.5, 68.6) 27.2 (26.9, 27.5) 90.5 (89.8, 91.2) 150 (148, 152) 84 (83, 85) 1.67 (1.59, 1.75) 1.23 (1.20, 1.25) 4.76 (4.66, 4.86) 2.71 (2.63, 2.79) 6.38 (6.16, 6.61) 17.78 (16.83, 18.77) 11.08 (10.45, 11.74) 1.60 (1.48, 1.74)
0.8239 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.9133 0.8825 <0.0001 <0.0001 <0.0001 <0.0001
Data were presented as mean (95% CI). Abbreviations: SBP, systolic blood pressure; DBP, systolic blood pressure; BMI, body mass index; FBG, fasting blood glucose; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol.
for the prevalence of MetS in comparison to the adiponectin and leptin levels alone in 77 Japanese male patients with diabetes mellitus [38]. In our study on older Chinese adults from the general population, the ability of leptin and L/A for
correctly classifying subjects with or without MetS are similar and better than adiponectin, and after adjusting for BMI, the L/ A showed to be better biomarker for MetS. The discrepancies may be due to the difference in the characteristics of the study
Table 2 – Correlation coefficients between adiponectin, leptin and leptin to adiponectin ratio with the components of MetS. Adiponectin r
Leptin p
r
L/A p
r
p
Men BMI Waist DBP SBP FBG HDL-C TG
0.254 0.285 0.047 0.015 0.118 0.238 0.204
<0.0001 <0.0001 0.1461 0.6418 0.0003 <0.0001 <0.0001
0.616 0.612 0.169 0.147 0.081 0.304 0.280
<0.0001 <0.0001 <0.0001 <0.0001 0.0123 <0.0001 <0.0001
0.608 0.617 0.158 0.127 0.113 0.343 0.311
<0.0001 <0.0001 <0.0001 0.0001 <0.0005 <0.0001 <0.0001
Women BMI Waist DBP SBP FBG HDL-C TG
0.177 0.216 0.106 0.060 0.121 0.255 0.186
<0.0001 <0.0001 0.0004 0.0481 0.0001 <0.0001 <0.0001
0.573 0.569 0.172 0.161 0.043 0.165 0.261
<0.0001 <0.0001 <0.0001 <0.0001 0.1572 <0.0001 <0.0001
0.511 0.529 0.180 0.147 0.096 0.259 0.289
<0.0001 <0.0001 <0.0001 <0.0001 0.0015 <0.0001 <0.0001
Abbreviations: BMI, body mass index; SBP, systolic blood pressure; DBP, systolic blood pressure; FBG, fasting blood glucose; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; L/A, leptin to adiponectin ratio.
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diabetes research and clinical practice 84 (2009) 27–33
Table 3 – Odds ratios and 95% confidence intervals for adiponectin, leptin, and leptin to adiponectin ratio with MetS. Variable
Adjusteda
Crude OR (95% CI)
p
OR (95% CI)
Male Adiponectin, 1 SD decrease Leptin, 1 SD increase L/A, 1 SD increase
1.79 (1.54, 2.08) 3.49 (2.68, 4.55) 3.71 (2.90, 4.74)
<0.001 <0.001 <0.001
1.61 (1.33, 1.95) 1.29 (0.96, 1.74) 1.83 (1.38, 2.45)
<0.001 0.089 <0.001
Female Adiponectin, 1 SD decrease Leptin, 1 SD increase L/A, 1 SD increase
1.58 (1.38, 1.81) 4.56 (3.46, 6.01) 3.63 (2.90, 4.55)
<0.001 <0.001 <0.001
1.48 (1.28, 1.73) 2.06 (1.53, 2.79) 2.32 (1.82, 2.96)
<0.001 <0.001 <0.001
a
p
Adjusted for age and BMI.
participants. The subjects in Mojiminiyi et al.’s study were patients with T2DM while the participants of Kumagai et al.’s study were male with either IGT or T2DM. Our participants were recruited from the residents from the general population. And the studies based on small-sizes may produce inconsistent results. More studies were warranted to elucidate which biomarker is better to differentiate individuals with and without MetS. Some lifestyle factors such as diet, smoking, alcohol drinking, and physical activity are thought to be important confounding factors of MetS. We compared the characteristics of participants between those with and without MetS. There were no significant differences between participants with and without MetS in both genders except for alcohol intake in men. After adjusting for those factors, the odds ratios remained similar. Therefore, we did not further adjust for those factors. We also performed the analyses on subsets data from the subjects who were not under medication for diabetes, hypertension or dyslipidemia and those who were free from DM. We also conducted the same analyses on the same participants using the updated ATP III definition for MetS proposed by American Heart Association/National Heart,
Lung, and Blood Institute (AHA/NHLBI) [39]. The results (data not shown) were similar to those of this paper. There are several limits in this study. Firstly, our study is cross-sectional and therefore it does not establish a cause and effect relationship. Secondly, since our study participants were older adults selected from 18 major cities in China, whether our findings can be deduced to other populations needs to be further assessed. Thirdly, there were different molecular weight multimer forms of adiponectin in the circulation, and some studies suggested the high molecular weight (HMW) multimers are the active forms of adiponectin, and are more useful than total adiponectin in evaluating the MetS and IR [40]. Though the results in this study showed leptin was a better biomarker for MetS than the total adiponectin, the roles of HMW multimers may be weakened by including adiponectin of low molecular weight. Further studies on comparison of HMW adiponectin and leptin associations with MetS are warranted. In conclusion, this study investigated the strength of adiponectin, leptin and L/A with MetS in older adults in major cities in China. The L/A and leptin were stronger associated with metabolic syndrome and its components than adipo-
Fig. 1 – Receiver operating characteristic curve for MetS by adiponectin, leptin and L/A stratified by sex.
32
diabetes research and clinical practice 84 (2009) 27–33
nectin with them. Our results imply that the L/A and leptin are better diagnostic markers for MetS than adiponectin. After adjusting for BMI, the L/A has better ability for correctly classifying subjects with and without MetS than adiponectin and leptin alone. Further studies are needed to elucidate our findings in different populations.
Conflict of interest None.
Acknowledgements This work was supported by research grant from National Natural Science Foundation of China (30671750). Zhiqiang Wang is supported by National Health and Medical Research Council of Australia (511013). The authors thank to all staff and participants of China National Nutrition and Health Survey in 2002.
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